A ‘Rule of Three’ for fragment-based lead discovery?

Congreve, Miles; Carr, Robin A. E.; Murray, Christopher W.; Jhoti, Harren

doi:10.1016/s1359-6446(03)02831-9

Cited by 1,248 publications

(1,005 citation statements)

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“…It is worth noting that the predicted water solubility of compounds bearing the D-proline moiety is still highly compatible with the ideal tolerance limits described for hit and lead compounds. 14,31 The contribution of the investigated chemical modifications to the arylsulfonamide scaffold allows the use of ZBGs different from the hydroxamic acid. Notably, 7* is endowed with a strong inhibitory activity toward MMP-12 and characterized by the carboxylic acid ZBG, which is generally associated with a lower affinity for zinc than hydroxamic acid, 25,27 but with a safer toxicity profile.…”

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confidence: 99%

Discovery of a New Class of Potent MMP Inhibitors by Structure-Based Optimization of the Arylsulfonamide Scaffold

Mori

Massaro

Calderone

et al. 2013

ACS Med. Chem. Lett.

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A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1′ aromatic portion and a D-proline residue bearing the zinc-binding group. The affinity improvement provided by these modifications led us to discover a nanomolar MMP inhibitor bearing a carboxylate moiety as zinc-binding group, which might be a promising lead molecule. Notably, a significant selectivity for MMP-8, MMP-12, and MMP-13 was observed with respect to MMP-1 and MMP-7. KEYWORDS: MMP, X-ray, synthesis, desolvation, docking, free energy M atrix metalloproteinases (MMPs) are a family of extracellular zinc-and calcium-dependent endopeptidases involved in the degradation and remodeling of extracellular matrix components, cell movement, proliferation, and tissues remodeling. 1,2 Aberrant MMPs activities are involved in several pathological states, and the design of synthetic MMP inhibitors represents an opportunity to develop new drug candidates. Recently, we reported on the use of a MMP-9 inhibitor for the potential treatment of Dry Eye Syndrome. 3 Here, we present a new scaffold for potent MMP inhibitors that was discovered by means of an integrated medicinal chemistry study, composed of computer-aided design, synthesis, X-ray analysis, and fluorimetric measurement of the binding affinity toward MMPs. A new strategy to improve the inhibitory activity toward MMPs by increasing the interactions with the S1′ pocket and, especially, by increasing the ligand solvation free energy is further presented. The different contributions to the binding affinity were further investigated with computational methods. 4 Human macrophagic metalloelastase (MMP-12) was selected as target because of its pathological relevance and of the availability of detailed structural information. Several potent inhibitors for MMP-12, such as phospinic peptides, sulfonamides, and bisphosphonic derivatives, have already been designed and tested. 5−10 For some of them a high selectivity toward MMP-12 has been observed, 5,6,8,10 although the molecular basis of this specificity is still a matter of research. Here, based on the classical arylsulfonamide scaffold, new MMP inhibitors were designed by introducing an ethylene linker between the sulfonamide moiety and the P1′ aromatic portion and by replacing the glycine residue with a D-proline within the zinc-binding group (ZBG). 11,12 The flexible linker was introduced to increase van der Waals interactions with the deep S1′ lipophilic cavity of MMPs, 13 without affecting the overall ligand binding mode. At the same time, the hydroxamate derivative of the rigid D-proline was evaluated as ZBGs for its possible favorable contribution to the solvation free energy of the ligand. It is interesting to note that these chemical substitutions do not sizably affect the ligand logP values, that remain within the tolerance limits described by the rule of three and...

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confidence: 99%

Discovery of a New Class of Potent MMP Inhibitors by Structure-Based Optimization of the Arylsulfonamide Scaffold

Mori

Massaro

Calderone

et al. 2013

ACS Med. Chem. Lett.

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“…All the ligand molecules show ADME properties within the acceptable range as shown in Table 6. These ligand molecules adhere to the Lipinski's rule of five [78] and Jorgenson's rule of three [79]. The ligand structures exhibit the properties in the acceptable range of Lipinski's rule of five (molecular weight <500, QPlogPo/w <5, hydrogen bond donor ≤5 and hydrogen bond acceptor ≤10) [60].…”

Section: Pharmacokinetic Properties Analysismentioning

confidence: 95%

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

et al. 2016

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Cancer progression is a global burden. The incidence and mortality now reach 30 million deaths per year. Several pathways of cancer are under investigation for the discovery of effective therapeutics. The present study highlights the structural details of the ubiquitin protein 'Ubiquitin-conjugating enzyme E2D4' (UBE2D4) for the novel lead structure identification in cancer drug discovery process. The evaluation of 3D structure of UBE2D4 was carried out using homology modelling techniques. The optimized structure was validated by standard computational protocols. The active site region of the UBE2D4 was identified using computational tools like CASTp, Q-site Finder and SiteMap. The hydrophobic pocket which is responsible for binding with its natural receptor ubiquitin ligase CHIP (C-terminal of Hsp 70 interacting protein) was identified through proteinprotein docking study. Corroborating the results obtained from active site prediction tools and protein-protein docking study, the domain of UBE2D4 which is responsible for cancer cell progression is sorted out for further docking study. Virtual screening with large structural database like CB_Div Set and Asinex BioDesign small molecular structural database was carried out. The obtained new ligand molecules that have shown affinity towards UBE2D4 were considered for ADME prediction studies. The identified new ligand molecules with acceptable parameters of docking, ADME are considered as potent UBE2D4 enzyme inhibitors for cancer therapy.

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“…Un exemple de ces molécules fragments est représenté dans la Figure 1. Historiquement, les molécules fragments ont été définies selon des critères physico-chimiques regroupés sous le nom de règle des trois, par analogie à la règle des cinq de Lipinski associée aux molécules « drug-like » administrables par voie orale [3]. Selon ces critères, une molécule fragment est définie comme une molécule organique de masse moléculaire inférieure à 300 g/mol, un coefficient de partage…”

Section: Concepts Et Définitionsunclassified

Le criblage de fragments

Krimm

2015

Med Sci (Paris)

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> Le criblage de molécules fragments a obtenu un succès incontestable ces dix dernières années pour la conception de médicaments et apparaît aujourd'hui comme une des voies incontournables pour générer des candidats dans le cas de cibles thérapeutiques ambitieuses et difficiles. Dans cette revue, les principaux concepts et les raisons du succès de la méthode des fragments sont rappelés, et les techniques et stratégies utilisées dans cette approche sont discutées. > octanol/eau logP inférieur à 3 1 , et un nombre de donneurs ainsi que d'accepteurs de liaisons hydrogène inférieur à 3. D'autres paramètres physicochimiques ont aussi été proposés par la suite, tels que la surface polaire des molécules, correspondant à la surface des atomes polaires (azote, oxygène, etc.), une valeur reliée à la capacité des molécules à pénétrer dans les cellules. La tendance actuelle est de considérer une masse moléculaire inférieure à 250 g/mol et une solubilité dans l'eau > 500 M comme les caracté-ristiques principales des fragments. Ces molécules fragments vont être criblées contre une cible thérapeu-tique choisie dans le cadre d'une pathologie particulière, ce qui permet d'identifier un certain nombre de fragments dits « points de départ » possibles, qui seront ensuite transformés en candidats médicaments. En raison de leur simplicité, ces molécules fragments ont généralement une affinité faible envers la cible protéique, c'est-à-dire une constante de dissociation du complexe protéine-fragment K D > 10-1 000 M. Dans la majorité des cas, aucune activité n'est détectable, et seules des mesures biophysiques permettent de s'assurer de l'interaction du fragment avec la protéine cible. L'enjeu de l'approche consiste alors à transformer le fragment initial (point de départ) en un candidat médicament qui pourra être testé en phase clinique, selon un processus rationnel et itératif s'appuyant sur des données structurales du complexe protéine-molécule. Les raisons du succès de la méthode des fragments sont multiples, et les avancées récentes obtenues en oncologie et en neurologie ( maladie 1 Logarithme du rapport des concentrations de la molécule étudiée dans l'octanol et dans l'eau, logP = log (C oct /C eau ).

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A ‘Rule of Three’ for fragment-based lead discovery?

Cited by 1,248 publications

References 10 publications

Discovery of a New Class of Potent MMP Inhibitors by Structure-Based Optimization of the Arylsulfonamide Scaffold

Discovery of a New Class of Potent MMP Inhibitors by Structure-Based Optimization of the Arylsulfonamide Scaffold

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

Le criblage de fragments

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